US4698431A - Hydroxypyridonate chelating agents - Google Patents

Hydroxypyridonate chelating agents Download PDF

Info

Publication number
US4698431A
US4698431A US06/796,815 US79681585A US4698431A US 4698431 A US4698431 A US 4698431A US 79681585 A US79681585 A US 79681585A US 4698431 A US4698431 A US 4698431A
Authority
US
United States
Prior art keywords
hopo
formula
sup
chelating agents
sub
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
US06/796,815
Inventor
Kenneth N. Raymond
Robert C. Scarrow
David L. White
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
US Department of Energy
Original Assignee
US Department of Energy
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by US Department of Energy filed Critical US Department of Energy
Priority to US06/796,815 priority Critical patent/US4698431A/en
Assigned to UNITED STATES OF AMERICA, AS REPRESENTED BY THE DEPARTMENT OF ENERGY, THE reassignment UNITED STATES OF AMERICA, AS REPRESENTED BY THE DEPARTMENT OF ENERGY, THE ASSIGNMENT OF ASSIGNORS INTEREST. Assignors: SCARROW, ROBERT C., RAYMOND, KENNETH N., WHITE, DAVID L.
Application granted granted Critical
Publication of US4698431A publication Critical patent/US4698431A/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/89—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to the ring nitrogen atom

Definitions

  • This invention relates generally to novel chelating agents, and more specifically relates to chelating agents which incorporate within their structures 1-hydroxy-2-pyridinone moieties and analogs thereof.
  • the invention also relates to methods of synthesizing and using such chelating agents.
  • Siderophores are highly selective ferric chelating agents synthesized and released by microorganisms to ensure the presence of sufficient iron for survival, in readily usable, i.e. solubilized, form.
  • the preparation of synthetic analogs of siderophores is of some interest, as such analogs could have important potential applications as clinical iron removal agents, particularly for patients who suffer from blood diseases such as betathalassemia, the treatment of which requires the regular transfusion of whole blood and results in the accumulation of massive tissue iron deposits.
  • synthetic analogs of siderophores are also potential chelators of tetravalent actinides, which present significant biological hazards associated with nuclear technology.
  • actinide chelating agents will be octadentate ligands, as opposed to the generally hexadentate siderophores.
  • Other uses, such as radionuclide chelation in nuclear medicine applications, for example, are also clearly possible.
  • the metal-binding ligands of siderophores are usually either catechols (dihydrobenzene analogues; Formula 1) or hydroxamic acids (Formula 2). ##STR1##
  • the siderophore enterobactin for example, incorporates three catechol groups as a hexadentate ligand. Synthetic analogs of catechol-based siderophores are also known. See, e.g., U.S. Pat. No. 4,530,963 to DeVoe et al., issued July 23, 1985.
  • the weak acidity of catechol and the required loss of two protons per catechol group at or about neutral pH limit the effectiveness of catechol-based ligands. It is therefore desirable to provide a medicinally useful chelating agent having a lower pK a that is more versatile than catechol-based compounds.
  • Uninegative ligands i.e., ligands having a single negative charge at neutral pH, are particularly desirable, in contrast to the corresponding highly charged ferric and plutonium catechol complexes.
  • the importance of both pK a and a monoprotic acid ligand is illustrated by the exponential nature of the proton-dependent metal-ligand complex formation constant (Eq. 1). ##STR2##
  • HOPO 1-hydroxy-2-pyridinone
  • Form 3 the ligand and its mono-anion (Formula 4) have a zwitterionic resonance form (Formula 5) that is isoelectronic with the catechol dianion.
  • the abbreviation "HOPO” will hereinafter be used to include 1-hydroxy-2-pyridinone analogues as well as isomers of tautomers thereof, in either protonated or deprotonated form.
  • the HOPO structure possesses some important synthetic advantages.
  • the 6-carboxylic acid structure (Formula 6) can be made in a straightforward manner, and further, the placement of functional groups at the 1, 2, and 6 positions makes possible the activation of the carboxylic acid moiety without the need for a protecting group at the N-hydroxyl position.
  • HOPO derivatives provided by the present invention also have the desired low pK a and are uninegative at neutral pH. ##STR3##
  • novel chelating agents which include HOPO-based monomers and dimers as well as larger structures such as HOPO-substituted desferrioxamine.
  • novel methods of synthesizing the HOPO-derived chelating agents are provided, as are methods of using the novel compounds.
  • the present invention first of all provides novel chelating agents capable of forming stable complexes with certain cations and selectively removing those cations from solution.
  • the inventors herein have demonstrated the effectiveness of novel chelating agents having 1-hydroxy-2-pyridinone ("HOPO") and related moieties incorporated within their structures.
  • HOPO-based compounds provide a number of advantages, and demonstrate superior utility as chelating agents having important pharmaceutical applications.
  • the novel HOPO-based chelators are uninegative at neutral pH and are soluble in water without the addition of carboxylic or sulfonic acid solubilizing groups.
  • the solubility properties of the HOPO-substituted compounds in combination with their relatively low pK a 's make them effective oral agents; present therapeutic agents, by contrast, are given by injection.
  • the new HOPO compounds display high binding constants for ferric ion, on the order of 10 26 to 10 27 M -3 for the tris (HOPO) Fe(III) comlexes, and are thus effective ligands for iron as well as for the other ions with similar coordination properties (e.g., the actinides).
  • Monomeric compounds of the invention include those given by the structure of Formula 7. ##STR4##
  • R is either an amide (Formula 7B) or a carboxylic acid (Formula 7A) moiety.
  • the compound is 1-hydroxy-2-pyridinone-6-carboxylic acid ("HOPO--CO 2 H").
  • R has the structure ##STR5## where R 1 and R 2 are preferably alkyl, aryl, or arylalkyl, and more preferably are either --H, --CH 3 , --CH 2 CH 3 , or --CH 2 -- ⁇ .
  • X may be hydrogen, an alkali metal ion, or a quaternary ammonium ion such as N(CH 3 ) 4 + .
  • Chelating agents of the present invention which incorporate two HOPO-type structures are given by Formula 9. ##STR6##
  • X is as given above for the monomers of Formula 7, and m is an integer between one and twenty.
  • m is three, and the structure is "3-HOPOCAM” (1-hydroxy-2-pyridinone structures separated by three methylene groups, somewhat analogous in structure to previously known catechoyl amide, or "CAM", sequestering agents).
  • chelating agents provided by the present invention include a number of HOPO-substituted amine and polyamine structures.
  • these HOPO-substituted compounds include those structures given by Formulae 10, 11, 12, and 13. ##STR7##
  • j, k, l, m and n are preferably integers between one and twenty.
  • m is three, n is four, and the structure is "3,4-HOPOCAM," a HOPO-substituted spermidine analogue.
  • a particularly preferred structure is "3,4,3-HOPOCAM," a HOPO-substituted spermine analogue, where l and n are three, and m is four.
  • Formula 12 gives a HOPO-substituted tris aminomethylbenzene analogue ("HOPO-MECAM”), with the "Z” moieties preferably being HOPO groups.
  • Formula 13 gives a HOPO-substituted analogue of desferrioxamine-B, in which j, l, and n are preferably two, while k and m are preferably five.
  • DF desferrioxamine
  • DFO dihydroxy-2-pyridinone analogue of the catechoyl amide structure
  • DFHOPOCAM dihydroxy-2-pyridinone analogue of the catechoyl amide structure
  • the chelating agents of this invention also include amine compounds which in addition to having at least one HOPO ligand are also substituted with catechol and catechol analogues.
  • the HOPO substituents could be replaced with the either of the structures given by Formulae 14 or 15, so long as one HOPO substituent remains present on the chelating structure.
  • chelating agents having polymeric backbones and at least one amine functionality to which a HOPO substituent is bonded through an amide-type linkage.
  • suitable polymers include poly(styrene-divinylbenzene), agarose (manufactured by Bio-Rad Corp., Richmond, CA, under the name "Affi-Gel”), and polyacrylamide.
  • the present invention also relates to novel methods of synthesizing the aforementioned chelating agents, as outlined below.
  • the monomeric compounds shown in Formula 7 may be synthesized according to Scheme I.
  • the 6-carboxylic acid derivative (Formula 7A) of 1-hydroxy-2-pyridinone is prepared from a 6-halopyridine-2-carboxylic acid (Formula 16; the compound is preferably 6-bromo, as shown) as follows.
  • the compound of Formula 16 is oxidized to yield the 1-oxide derivative (Formula 17); preferred oxidizing agents include a mixture of trifluoroacetic acid and hydrogen peroxide.
  • the 1-oxide of Formula 17 is then dissolved in a hydroxide solution such as aqueous potassium hydroxide and allowed to remain for at least one hour at an elevated temperature of at least about 60° C.
  • the solution is then cooled and treated with acid; the 6-carboxylic acid (Formula 7A) may then be isolated, e.g. by filtration, purified, and dried (see Example 1).
  • the HOPO amide monomer shown in Formula 7B may then be prepared from the 6-carboxylic acid compound of Formula 7A as follows.
  • a quantity of the 6-carboxylic acid derivative is suspended in an inert and preferably polar solvent such as tetrahydrofuran (THF) or other ethereal solvents.
  • a preferred ratio of 7A to solvent is about 1:10.
  • Phosgene gas is bubbled in until the suspended starting material is dissolved; alternatively, compounds which generate phosgene gas may be admixed into the solution. After a reaction period of between about 5 min. and about 30 min.
  • These polydentate HOPO-substituted amines are prepared starting from the 6-carboxylic acid HOPO monomer of Formula 7A, which is dissolved in an N,N'-dialkylamide such as dimethylacetamide (DMAA) or dimethylformamide (DMF). The solution is cooled in an ice bath, and an approximately equimolar amount of phosgene in an inert, organic, and preferably polar solvent (e.g., ethereal solvents such as THF) is added. The resulting reaction is mildly exothermic and produces some gas evolution.
  • N,N'-dialkylamide such as dimethylacetamide (DMAA) or dimethylformamide (DMF).
  • DMAA dimethylacetamide
  • DMF dimethylformamide
  • reaction mixture After at least about five minutes, a stoichiometric amount of triethylamine is added to the reaction mixture, producing a complex presumably having the structure ##STR11##
  • the reaction mixture is stirred for at least about 5 min., preferably about 30 min., at a temperature ranging from about 5°-60° C., and preferably below about 20° C.
  • a predetermined amount of the amine compound which will provide the "backbone" of the chelating agent is then added and the reaction mixture is stirred for at least 1 hr. at room temperature to ensure complete reaction. While any number of amines can be used in this reaction to effect production of HOPO-substituted chelating agents, preferred amines are those which correspond to the structures of Formulae 10-13.
  • Particularly preferred amines are the polyamines 1,3-diaminopropane (NH 2 --(CH 2 ) 3 --NH 2 ), spermidine (NH 2 --(CH 2 ) 3 --NH--(CH 2 ) 4 --NH 2 ), spermine (NH 2 --(CH 2 ) 3 --NH--(CH 2 ) 4 --NH--(CH 2 ) 3 --NH 2 ), tris aminomethylbenzene (see Formula 12) and the polymeric monoamine desferrioxamine (see Formula 13).
  • the reaction mixture is filtered to remove precipitated Et 3 N.HCl, and the solvent is removed.
  • the viscous residue is purified, preferably by extraction and/or column chromatography.
  • amines which may be used in the above synthetic procedure include compounds generally given by Formulae 10-13 but having one or more catechol-type ligands (see Formulae 14 and 15) in addition to at least one HOPO group.
  • Hydrocarbon polymers having at least one amino group may also be used (e.g., agarose, polyacrylamide, and other similar compounds).
  • the mono- and bis-HOPO compounds are white to very pale yellow solids. While not necessarily crystalline, they can be easily isolated as freely flowing powders with sharp melting points. As the number of pendent HOPO moieties is increased, however, the solids become more and more hygroscopic, glassy in nature, and difficult to characterize.
  • the most distinctive feature of their NMR spectra is the set of three doublets in the aromatic region arising from the HOPO ring protons (see Examples 5 and 6).
  • Their IR spectra display a strong band at ca. 1650 cm. -1 due to overlapping amide and ring carbonyl absorptions. A ring stretching band at 1570 cm -1 is also observed.
  • the HOPO derivative of desferrioxamine displays a maximum at 1622 cm -1 presumably due to overlap with the hydroxamic acid carbonyl bands.
  • the novel HOPO-substituted amine compounds are moderately to very soluble in water (on the order of 1 g/10 ml at room temperature, 5g/10 ml at 80° C.). They are weakly acidic (having pK a 's on the order of 5), and the pH of saturated aqueous solution is typically about three. They form complexes with metal ions, e.g., Th +4 , Zn +2 , and Fe +3 .
  • the compounds of the present invention may be used in a variety of applications.
  • the compounds are primarily useful in selectively removing cations from solution, and are particularly useful with +2, +3 and +4 cations.
  • these HOPO-substituted compounds are exemplary ferric ion chelators and are thus useful in the removal of excess iron from the body.
  • preferred doses range from about 20 mg/kg to about 200 mg/kg.
  • the major route of excretion is primarily through the kidneys; the relative potency here (highest fraction of iron excreted) is greatest for the HOPO-substituted desferrioxamine (DFHOPOCAM; see Example 8). (Iron removal from transferrin is also quite rapid--see Example 11.)
  • novel chelators are also effective chemical agents for decorporation of actinides and other chemically similar ions, as they have been shown to promote significant excretion of actinides such as Pu(IV). Again, while all of the inventive compounds are quite effective in this regard, DFHOPOCAM seems to produce the most effective removal of such ions (see Example 12).
  • Infrared spectra were obtained using a Perkin-Elmer Model 283 spectrophotometer. NMR spectra were obtained on Jeol FX-90Q (90 MHz) or UCB-250 (250 MHz) spectrometers. Electron impact ionization (EI) mass spectra were obtained using an AEI MS-12 instrument, while a Finnigan 4000 instrument provided CI mass spectra using methane. A Kratos MS-50 Mass Spectrometer using a xenon beam was employed to acquire fast atom bombardment ionization ( + FAB) mass spectra. Microanalyses were performed by the Microanalytical Laboratory, Chemistry Dept., University of California, Berkeley, Calif. 94720. C, H, and N analyses were within 0.4% of the calculated values for all new compounds, unless otherwise noted.
  • HPLC HPLC was performed on a Beckman-Altex Model 340 system using an Altex Ultrasphere ODS precolumn (4.6 mm id ⁇ 40 mm) and column (4.6 mm id ⁇ 150 mm) for analytical work. A similar 10 mm id ⁇ 250 mm column was used for preparative chromatography. Unless otherwise stated, the mobile phase was a methanol-water gradient (0 to 100% MeOH over 10 minutes), with each component 0.025M in formic acid (pH 2.8).
  • 1-Hydroxy-2-(1H)-pyridinone-6-carboxylic acid was prepared as described in Example 1.
  • Triethylamine, THF, and N,N-dimethylacetamide (DMAA) were purified by distillation under nitrogen from sodium, potassium benzophenone ketyl, and phosphorus pentoxide, respectively.
  • Spermine and spermidine were obtained from The Ames Laboratories, Inc., Milford, CT.
  • Desferrioxamine was obtained from Ciba-Geigy ("Desferal," a trademark of Ciba-Geigy Corp.).
  • Other organic reagents were purchased from the Aldrich Chemical Co. and used without further purification.
  • Solutions of phosgene in THF were prepared by bubbling the gas into a weighed quantity of anhydrous solvent cooled in an ice bath until the desired mass had been dissolved.
  • the titer of this solution was determined by reacting an aliquot with excess aniline in THF and quantifying the resulting carbanilide by HPLC.
  • DFHOPOCAM was tested for its effectiveness in removing iron from iron-loaded mice.
  • the mice tested had undergone three transfusions over five days of heat-treated canine red blood cells. Both low i.p. doses (about 20 mg/kg) and high doses (about 200 mg/kg) were administered, in aqueous solution. Analysis of daily excreta during a five-day recovery period disclosed reversal of most of the damage to excretory pathways resulting from the excess metabolic iron.
  • Orange-red hexagonal needles were obtained by evaporating a solution of amorphous material in 1:1 MeOH:CH 2 Cl 2 containing a small amount (1-2%) of water. Analysis (C 48 H 42 N 12 Fe 2 .2CH 3 OH.H 2 O) C, H, N.
  • the large cell volume indicates eight Fe 2 L 3 units per unit cell. Because of the large asymmetric unit, the structure of the monoclinic crystals was not pursued.
  • Solution of the structure indicates that the compound consists of molecules containing two high-spin ferric ions and three 3-HOPOCAM ligands arranged such that the octahedral coordination requirement of each iron atom is satisfied by the oxygen atoms of three bidentate hydroxypyridonate groups.
  • Each 3-HOPOCAM ligand bridges between the two iron atoms.
  • 3HOPOCAM As a ferri ion chelator was evaluated in terms of its potential for removing iron from transferrin.
  • the relative ironbinding abilities of the ligands were ranked by the pM value, defined as -log [Fe +3 ] of pH 7.4 solution that is 10 -5 M in total ligand and 10 -6 M in total iron.
  • the pM for 3HOPOCAM was determined (by binding competition experiments with EDTA) to be 21.7, about 4 to 14 units lower than the pM value for siderophores containing three bidentate catechol or hydroxamate groups.
  • the novel chelating agents of the present invention were tested for their effectiveness in promoting excretion of 238 Pu(IV) in mice as follows. Groups of five mice each received an intravenous injection of 0. ml of 238 Pu(IV) in citrate buffer, 9250 Bq/kg body wt. One hour later 30 ⁇ mole/kg of ligand (120 ⁇ mole/kg of monomeric ligands) was injected intraperitoneally in 0.5 ml of saline. The mice were killed 24 h after the Pu injection, frozen, and dissected after partial thawing. The 238 Pu in skeleton, tissues, and separated excreta was determined by counting of the 234 U L xrays.
  • Results of the initial tests of potency and toxicity of the ligands tested are summarized in Table 3, which also includes data for the baseline ligand, CaNa 3DTPA and the Puinjected controls (no ligands) killed at 1 hr or 24 hr after injection. Results using iron and zinc complexes of the ligands are summarized in Table 4. As illustrated by the data compile in Tables 3 and 4, all the novel chelating agents provided effective Pu removal, although HOPOsubstituted desferrioxamine proved to be the most effective Pu removal agent (86% of newly injected Pu excreted in 24 hr). Furthermore, none of the desferrioxamine derivatives proved to be acutely toxic, even at the relatively high dose of 1000 ⁇ mole/kg.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pyridine Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

Chelating agents having 1-hydroxy-2-pyridinone (HOPO) and related moieties incorporated within their structures, including polydentate HOPO-substituted polyamines such as spermidine and spermine, and HOPO-substituted desferrioxamine. The chelating agents are useful in selectively removing certain cations from solution, and are particularly useful as ferric ion and actinide chelators. Novel syntheses of the chelating agents are provided.

Description

FIELD OF THE INVENTION
This invention relates generally to novel chelating agents, and more specifically relates to chelating agents which incorporate within their structures 1-hydroxy-2-pyridinone moieties and analogs thereof. The invention also relates to methods of synthesizing and using such chelating agents.
BACKGROUND OF THE INVENTION
The Government has rights in this invention pursuant to Contract No. DE-AC03-76SF-00098 awarded by the U.S. Department of Energy.
Siderophores are highly selective ferric chelating agents synthesized and released by microorganisms to ensure the presence of sufficient iron for survival, in readily usable, i.e. solubilized, form. The preparation of synthetic analogs of siderophores is of some interest, as such analogs could have important potential applications as clinical iron removal agents, particularly for patients who suffer from blood diseases such as betathalassemia, the treatment of which requires the regular transfusion of whole blood and results in the accumulation of massive tissue iron deposits. Because of the similarity in coordination properties between the ferric ion and the tetravalent actinides, synthetic analogs of siderophores are also potential chelators of tetravalent actinides, which present significant biological hazards associated with nuclear technology. Normally, such actinide chelating agents will be octadentate ligands, as opposed to the generally hexadentate siderophores. Other uses, such as radionuclide chelation in nuclear medicine applications, for example, are also clearly possible.
The metal-binding ligands of siderophores are usually either catechols (dihydrobenzene analogues; Formula 1) or hydroxamic acids (Formula 2). ##STR1##
The siderophore enterobactin, for example, incorporates three catechol groups as a hexadentate ligand. Synthetic analogs of catechol-based siderophores are also known. See, e.g., U.S. Pat. No. 4,530,963 to DeVoe et al., issued July 23, 1985. However, the weak acidity of catechol and the required loss of two protons per catechol group at or about neutral pH limit the effectiveness of catechol-based ligands. It is therefore desirable to provide a medicinally useful chelating agent having a lower pKa that is more versatile than catechol-based compounds. Uninegative ligands, i.e., ligands having a single negative charge at neutral pH, are particularly desirable, in contrast to the corresponding highly charged ferric and plutonium catechol complexes. The importance of both pKa and a monoprotic acid ligand is illustrated by the exponential nature of the proton-dependent metal-ligand complex formation constant (Eq. 1). ##STR2##
Derivatives of 1-hydroxy-2-pyridinone (Formula 3; "HOPO") are of particular interest, since the ligand and its mono-anion (Formula 4) have a zwitterionic resonance form (Formula 5) that is isoelectronic with the catechol dianion. The abbreviation "HOPO" will hereinafter be used to include 1-hydroxy-2-pyridinone analogues as well as isomers of tautomers thereof, in either protonated or deprotonated form.
The HOPO structure possesses some important synthetic advantages. The 6-carboxylic acid structure (Formula 6) can be made in a straightforward manner, and further, the placement of functional groups at the 1, 2, and 6 positions makes possible the activation of the carboxylic acid moiety without the need for a protecting group at the N-hydroxyl position. HOPO derivatives provided by the present invention also have the desired low pKa and are uninegative at neutral pH. ##STR3##
SUMMARY OF THE INVENTION
Accordingly, it is an object of the present invention to provide novel chelating agents which will form highly stable complexes with cations such as Fe (III) and Pu (IV), and which will promote significant excretion of such cations.
It is another object of the invention to provide chelating agents which are relatively acidic and incorporate monoprotic ligand groups.
It is still another object of the invention to provide chelating agents which incorporate 1-hydroxy-2-pyridinone moieties within their structures.
It is a further object of the invention to provide methods of synthesizing the novel HOPO-based chelating agents.
It is still a further object of the invention to provide methods of using the novel chelating agents.
In one aspect of the present invention, novel chelating agents are provided which include HOPO-based monomers and dimers as well as larger structures such as HOPO-substituted desferrioxamine. In other aspects of the invention, novel methods of synthesizing the HOPO-derived chelating agents are provided, as are methods of using the novel compounds.
DETAILED DESCRIPTION OF THE INVENTION
The present invention first of all provides novel chelating agents capable of forming stable complexes with certain cations and selectively removing those cations from solution. The inventors herein have demonstrated the effectiveness of novel chelating agents having 1-hydroxy-2-pyridinone ("HOPO") and related moieties incorporated within their structures. HOPO-based compounds provide a number of advantages, and demonstrate superior utility as chelating agents having important pharmaceutical applications. In contrast to their catechol analogues, the novel HOPO-based chelators are uninegative at neutral pH and are soluble in water without the addition of carboxylic or sulfonic acid solubilizing groups. The solubility properties of the HOPO-substituted compounds in combination with their relatively low pKa 's make them effective oral agents; present therapeutic agents, by contrast, are given by injection. The new HOPO compounds display high binding constants for ferric ion, on the order of 1026 to 1027 M-3 for the tris (HOPO) Fe(III) comlexes, and are thus effective ligands for iron as well as for the other ions with similar coordination properties (e.g., the actinides).
Monomeric compounds of the invention include those given by the structure of Formula 7. ##STR4##
In Formula 7, R is either an amide (Formula 7B) or a carboxylic acid (Formula 7A) moiety. In the carboxylic acid form, the compound is 1-hydroxy-2-pyridinone-6-carboxylic acid ("HOPO--CO2 H"). In the amide form, R has the structure ##STR5## where R1 and R2 are preferably alkyl, aryl, or arylalkyl, and more preferably are either --H, --CH3, --CH2 CH3, or --CH2 --φ. In both forms, X may be hydrogen, an alkali metal ion, or a quaternary ammonium ion such as N(CH3)4 +.
Chelating agents of the present invention which incorporate two HOPO-type structures are given by Formula 9. ##STR6## In Formula 9, X is as given above for the monomers of Formula 7, and m is an integer between one and twenty. In a particularly preferred form, m is three, and the structure is "3-HOPOCAM" (1-hydroxy-2-pyridinone structures separated by three methylene groups, somewhat analogous in structure to previously known catechoyl amide, or "CAM", sequestering agents).
Other chelating agents provided by the present invention include a number of HOPO-substituted amine and polyamine structures. Examples of these HOPO-substituted compounds include those structures given by Formulae 10, 11, 12, and 13. ##STR7## In Formulae 10 through 13, j, k, l, m and n are preferably integers between one and twenty. In a particularly preferred embodiment of the compound given by Formula 10, m is three, n is four, and the structure is "3,4-HOPOCAM," a HOPO-substituted spermidine analogue. With regard to Formula 11, a particularly preferred structure is "3,4,3-HOPOCAM," a HOPO-substituted spermine analogue, where l and n are three, and m is four. Formula 12 gives a HOPO-substituted tris aminomethylbenzene analogue ("HOPO-MECAM"), with the "Z" moieties preferably being HOPO groups. Formula 13 gives a HOPO-substituted analogue of desferrioxamine-B, in which j, l, and n are preferably two, while k and m are preferably five.
This substituted desferrioxamine (known variously as "DF," "DFO," "DF-B" and "DFOM") compound will hereinafter be referred to as "DFHOPOCAM" (desferrioxamine 1-hydroxy-2-pyridinone analogue of the catechoyl amide structure). This latter compound represents a particularly preferred embodiment of the invention, as it has been demonstrated to be extremely effective both in ferric ion chelation and in the decorporation of actinides such as Pu(IV).
The chelating agents of this invention also include amine compounds which in addition to having at least one HOPO ligand are also substituted with catechol and catechol analogues. Thus, in the compounds of Formulae 10-13 above, the HOPO substituents could be replaced with the either of the structures given by Formulae 14 or 15, so long as one HOPO substituent remains present on the chelating structure. ##STR8##
Also included in the present invention are chelating agents having polymeric backbones and at least one amine functionality to which a HOPO substituent is bonded through an amide-type linkage. Examples of suitable polymers here include poly(styrene-divinylbenzene), agarose (manufactured by Bio-Rad Corp., Richmond, CA, under the name "Affi-Gel"), and polyacrylamide.
The present invention also relates to novel methods of synthesizing the aforementioned chelating agents, as outlined below.
The monomeric compounds shown in Formula 7 may be synthesized according to Scheme I. ##STR9## The 6-carboxylic acid derivative (Formula 7A) of 1-hydroxy-2-pyridinone is prepared from a 6-halopyridine-2-carboxylic acid (Formula 16; the compound is preferably 6-bromo, as shown) as follows. The compound of Formula 16 is oxidized to yield the 1-oxide derivative (Formula 17); preferred oxidizing agents include a mixture of trifluoroacetic acid and hydrogen peroxide. The 1-oxide of Formula 17 is then dissolved in a hydroxide solution such as aqueous potassium hydroxide and allowed to remain for at least one hour at an elevated temperature of at least about 60° C. The solution is then cooled and treated with acid; the 6-carboxylic acid (Formula 7A) may then be isolated, e.g. by filtration, purified, and dried (see Example 1).
The HOPO amide monomer shown in Formula 7B may then be prepared from the 6-carboxylic acid compound of Formula 7A as follows. A quantity of the 6-carboxylic acid derivative is suspended in an inert and preferably polar solvent such as tetrahydrofuran (THF) or other ethereal solvents. A preferred ratio of 7A to solvent is about 1:10. Phosgene gas is bubbled in until the suspended starting material is dissolved; alternatively, compounds which generate phosgene gas may be admixed into the solution. After a reaction period of between about 5 min. and about 30 min. at a temperature ranging from about 10° to about 80° C., preferably approximating 25° C., volatiles, including any excess phosgene, are removed from the reaction mixture in vacuo. The viscous residue obtained is dissolved in an inert, organic, and preferably polar solvent, and added to a solution of amine. An amine of formula NHR1 R2 will provide the general structure of Formula 7B; dimethylamine, for example, will yield N,N'-dimethyl-1-hydroxy-2(1H)-pyridinone- 6-carboxamide (see Example 2). After reaction with the amine is allowed to proceed at room temperature for at least about several hours, the product of Formula 7B is isolated, purified, and dried. (The inventors herein postulate that the intermediate structure involved in the foregoing reaction is a cyclic anhydride having the structure ##STR10## which reacts with the amine compound to yield the HOPO-amide derivative.)
It is also possible to carry out the above reaction producing the HOPO-amide monomer of Formula 7B using thionyl chloride. See, e.g., Scarrow et al., "Ferric Ion Sequestering Agents. 13. Synthesis, Structures and Thermodynamics of Complexation of Cobalt (III) and Iron (III) Tris Complexes of Several Chelating Hydroxypyridinones," J. Inorg. Chem. 24 (6), 954-967, at 956 (1985), the disclosure of which is hereby incorporated by reference in its entirety. It has proved quite difficult, however, to prepare multiply HOPO-substituted compounds using thionyl chloride, primarily because of solubility limitations. Accordingly, the inventors herein propose a novel synthesis whereby amine compounds having a plurality of HOPO ligands incorporated within their structures are provided.
These polydentate HOPO-substituted amines are prepared starting from the 6-carboxylic acid HOPO monomer of Formula 7A, which is dissolved in an N,N'-dialkylamide such as dimethylacetamide (DMAA) or dimethylformamide (DMF). The solution is cooled in an ice bath, and an approximately equimolar amount of phosgene in an inert, organic, and preferably polar solvent (e.g., ethereal solvents such as THF) is added. The resulting reaction is mildly exothermic and produces some gas evolution. After at least about five minutes, a stoichiometric amount of triethylamine is added to the reaction mixture, producing a complex presumably having the structure ##STR11## The reaction mixture is stirred for at least about 5 min., preferably about 30 min., at a temperature ranging from about 5°-60° C., and preferably below about 20° C. A predetermined amount of the amine compound which will provide the "backbone" of the chelating agent is then added and the reaction mixture is stirred for at least 1 hr. at room temperature to ensure complete reaction. While any number of amines can be used in this reaction to effect production of HOPO-substituted chelating agents, preferred amines are those which correspond to the structures of Formulae 10-13. Particularly preferred amines are the polyamines 1,3-diaminopropane (NH2 --(CH2)3 --NH2), spermidine (NH2 --(CH2)3 --NH--(CH2)4 --NH2), spermine (NH2 --(CH2)3 --NH--(CH2)4 --NH--(CH2)3 --NH2), tris aminomethylbenzene (see Formula 12) and the polymeric monoamine desferrioxamine (see Formula 13). The reaction mixture is filtered to remove precipitated Et3 N.HCl, and the solvent is removed. The viscous residue is purified, preferably by extraction and/or column chromatography. Mono- and bis [1-hydroxy-2(1H)-6-carbonyl]amines prepared by this procedure are best recrystallized from water, while tris- and tetrakis-compounds (generally hygroscopic, glassy solids) are best purified by high performance liquid chromatography (HPLC).
Other amines which may be used in the above synthetic procedure include compounds generally given by Formulae 10-13 but having one or more catechol-type ligands (see Formulae 14 and 15) in addition to at least one HOPO group. Hydrocarbon polymers having at least one amino group may also be used (e.g., agarose, polyacrylamide, and other similar compounds).
Properties of the novel compounds:
Physical Properties: The mono- and bis-HOPO compounds (e.g., Formulae 7 and 8) are white to very pale yellow solids. While not necessarily crystalline, they can be easily isolated as freely flowing powders with sharp melting points. As the number of pendent HOPO moieties is increased, however, the solids become more and more hygroscopic, glassy in nature, and difficult to characterize. The most distinctive feature of their NMR spectra is the set of three doublets in the aromatic region arising from the HOPO ring protons (see Examples 5 and 6). Their IR spectra display a strong band at ca. 1650 cm.-1 due to overlapping amide and ring carbonyl absorptions. A ring stretching band at 1570 cm-1 is also observed. However, the HOPO derivative of desferrioxamine, displays a maximum at 1622 cm-1 presumably due to overlap with the hydroxamic acid carbonyl bands.
Chemical Properties. The novel HOPO-substituted amine compounds are moderately to very soluble in water (on the order of 1 g/10 ml at room temperature, 5g/10 ml at 80° C.). They are weakly acidic (having pKa 's on the order of 5), and the pH of saturated aqueous solution is typically about three. They form complexes with metal ions, e.g., Th+4, Zn+2, and Fe+3.
As mentioned above, the compounds of the present invention may be used in a variety of applications. The compounds are primarily useful in selectively removing cations from solution, and are particularly useful with +2, +3 and +4 cations. For example, these HOPO-substituted compounds are exemplary ferric ion chelators and are thus useful in the removal of excess iron from the body. For this latter application, preferred doses range from about 20 mg/kg to about 200 mg/kg. The major route of excretion is primarily through the kidneys; the relative potency here (highest fraction of iron excreted) is greatest for the HOPO-substituted desferrioxamine (DFHOPOCAM; see Example 8). (Iron removal from transferrin is also quite rapid--see Example 11.)
The novel chelators are also effective chemical agents for decorporation of actinides and other chemically similar ions, as they have been shown to promote significant excretion of actinides such as Pu(IV). Again, while all of the inventive compounds are quite effective in this regard, DFHOPOCAM seems to produce the most effective removal of such ions (see Example 12).
Experimental Methods:
Infrared spectra were obtained using a Perkin-Elmer Model 283 spectrophotometer. NMR spectra were obtained on Jeol FX-90Q (90 MHz) or UCB-250 (250 MHz) spectrometers. Electron impact ionization (EI) mass spectra were obtained using an AEI MS-12 instrument, while a Finnigan 4000 instrument provided CI mass spectra using methane. A Kratos MS-50 Mass Spectrometer using a xenon beam was employed to acquire fast atom bombardment ionization (+ FAB) mass spectra. Microanalyses were performed by the Microanalytical Laboratory, Chemistry Dept., University of California, Berkeley, Calif. 94720. C, H, and N analyses were within 0.4% of the calculated values for all new compounds, unless otherwise noted.
HPLC was performed on a Beckman-Altex Model 340 system using an Altex Ultrasphere ODS precolumn (4.6 mm id×40 mm) and column (4.6 mm id×150 mm) for analytical work. A similar 10 mm id×250 mm column was used for preparative chromatography. Unless otherwise stated, the mobile phase was a methanol-water gradient (0 to 100% MeOH over 10 minutes), with each component 0.025M in formic acid (pH 2.8).
1-Hydroxy-2-(1H)-pyridinone-6-carboxylic acid was prepared as described in Example 1. Triethylamine, THF, and N,N-dimethylacetamide (DMAA) were purified by distillation under nitrogen from sodium, potassium benzophenone ketyl, and phosphorus pentoxide, respectively. Spermine and spermidine were obtained from The Ames Laboratories, Inc., Milford, CT. Desferrioxamine was obtained from Ciba-Geigy ("Desferal," a trademark of Ciba-Geigy Corp.). Other organic reagents were purchased from the Aldrich Chemical Co. and used without further purification.
Solutions of phosgene in THF were prepared by bubbling the gas into a weighed quantity of anhydrous solvent cooled in an ice bath until the desired mass had been dissolved. The titer of this solution was determined by reacting an aliquot with excess aniline in THF and quantifying the resulting carbanilide by HPLC.
EXAMPLE 1
Preparation of 1-hydroxy-2(1H)-pyridinone-6-carboxylic acid (Formula 7A): A 9.7 g (0.048 mol.) portion of 6-bromopyridine-2-carboxylic acid was added to a solution of 125 ml of CF3 COOH and 18 ml of 30% H2 O2 and heated to 80° C. for 6.5 h. The reaction mixture was concentrated to ca. 25 ml by rotary evaporation and then added to 1 l of water. The product immediately precipitated as a finely divided, white crystalline solid. It was isolated by filtration, washed with water, and dried in vacuo. This yielded 10.2 g of product, 2-bromopyridine-6-carboxylic acid (Formula 16), mp 180° C. dec. Anal. Calcd. for C6 H4 BrNO3 : C, 33.05; H, 1.85; Br, 36.65; N, 6.43. Found: C, 33.30; H, 1.88; Br, 36.37; N, 6.52.
A 10.1 g (0.046 mol.) portion of the 2-bromopyridine-6-carboxylic acid prepared above was dissolved in 175 ml of a 10% aqueous KOH solution, and the resulting solution was maintained at 80° C. overnight and then cooled in an ice bath and treated with 85 ml of concentrated HCl. The white suspended solid was isolated by filtration, washed with dilute HCl followed by three 15-ml portions of water, and then dried in vacuo to yield 6.21 g (86.4%) of 1-hydroxy-2(1H)-pyridinone-6-carboxylic acid (Formula 7A), mp 216° C. dec. Anal. Calcd. for C6 H5 NO4 : C, 46.45; H, 3.25; N, 9.03. Found: C, 46.29; H, 3.26; N, 8.96.
EXAMPLE 2
Preparation of N,N'-dimethyl-1-hydroxy-2(1H)-pyridinone-6-carboxamide (Formula 7B; R1 ═R2 ═CH3): A 3-neck 25 ml flask equipped with a magnetic stirrer, subsurface gas inlet, and gas outlet was charged with 10 ml of THF and 0.60 g (3.9 mmoles) of 1-hydroxy-2(1H)-pyridinone-6-carboxylic acid (Formula 7A). Phosgene gas was bubbled in until the suspended starting material had dissolved. After a reaction period of 15 min at 25° C., volatiles were removed from the reaction mixture in vacuo. The viscous residue was dissolved in THF, and this solution was added to 20 ml of THF saturated with dimethylamine. Additional gas was bubbled into the solution during the addition to ensure an excess. The resulting suspension was filtered to remove Et3 N.HCl, and solvent and excess amine were removed on a rotary evaporator. The residue was dissolved in 7 ml of water, and this solution was applied to a 1.45 cm id×14 cm long column of AG 50-X8 ion exchange resin (Bio-Rad) in the H+ form and eluted with water. HCl appeared first, followed by a light yellow fraction that gave a red color when treated with ferric ion. Removal of water from the latter fraction left 0.42 g (60%) of light yellow product (Formula 7B), mp 165°-168° C. EI Mass. Spec.: 182 (M+, 1), 166 (88), 122 (49), 72 (92). 1 H NMR: δ 2.95 (s; 3; NCH3), 3.05 (s; 3; NCH3), 4.77 (bs; 1; NOH), 6.29 (dd; 1; J=1.6, 7.03; pyr-3- or 5-H), 6.59 (dd; 1; J=1.6, 9.22; pyr-5- or 3-H), 7.39 (dd; 1; J=7.03, 9.22; pyr-4-H) (in Me2 SO-D6).
EXAMPLE 3
Preparation of a HOPO amide monomer (Formula 7B; R1 ═H, R2 ═benzyl): A dry 250 ml 3-neck round-bottom flask equipped with a magnetic stirrer, gas inlet, addition funnel, and thermometer was flushed with nitrogen and charged with 3.10 g (20 mmoles) of 1-hydroxy-2(1H)-pyridinone-6-carboxylic acid (Formula 7A) and 50 ml of DMAA. The solution was cooled in an ice bath and then treated dropwise with 21 mmoles of phosgene in THF solution. The resulting mildly exothermic reaction produced some gas evolution and a bright yellow reaction mixture. The addition of 8.71 g (86 mmoles) of triethylamine also gave an exothermic reaction, and a white precipitate was formed. After being stirred for 30 min. at 5°-10° C., this suspension was treated with 16 meq of benzylamine. The resulting mixture was allowed to stir overnight at room temperature. The reaction mixture was then filtered to remove precipitated Et3 N.HCl, and solvent was removed from the filtrate on a rotary evaporator. The viscous, amber residue was partitioned between 50 ml each of chloroform and dilute aqueous NH3 (pH 10). The chloroform extract, containing non-polar by-products, was discarded; the aqueous phase was concentrated to about 20 ml. This solution then was chromatographed on a 2.5 cm id×20 cm long column of Ag 50-X8 ion exchange resin in the H+ form eluting with water. HCl eluted first, followed immediately by an acidic (pH 1.5) yellow fraction that gave a bright red-orange precipitate upon reaction with Fe+3. This fraction contained essentially only the carboxylic acid of Formula 7A, and about 0.6 g (20%) could be recovered upon evaporation. The pH of the eluant then began to rise to about 3, and the color of the Fe+3 spot test became brown-red. This signaled elution of the product-containing fraction. This was usually contamined with small amounts of 7A, as well as by-products. These contaminants were removed upon recrystallization in water, yielding a pure product, mp 129°-130° C. + FAB Mass. Spec.: 259 (M+ +Na, 3), 245)M+ +H, 100), 229 (79). 1 H NMR: δ 4.40 (bs; 1; NCH2), 4.47 (bs; 1; NCH2), 6.34 (d; 1; J=6.2; pyr-3- or 5-H), 6.57 (d; 1; J=7.8; pyr-5- or 3-H), 7.32 (m; 6; C6 H5 and pyr-4-H), 9.37 (bt; 1; J=7; CONH) (in Me2 SO-D6).
EXAMPLE 4
Preparation of 3-HOPOCAM (Formula 9; m=3, X=Na): A procedure identical to that carried out in Example 3 was followed; however, the benzylamine used in that procedure was replaced by 1,3-diaminopropane (H2 N-(CH2)3 -NH2). The product, 3-HOPOCAM, was recrystallized in water and obtained in about a 50% yield, mp 206°-207° C. + FAB Mass. Spec.: 349 (M+ +H, 100), 333 (61), 317 (15). 1 H NMR: δ 1.76 (q; 2; J=6.5; CH2 CH2 CH2), 3.26 (d(t); 4; J=4.2, 6.5; NHCH2 CH2), 6.30 (dd; 2; J=1.6, 6.5; pyr-3- or 5-H), 6.56 (dd; 2; J=1.6, 8.8; pyr-5- or 3-H), 7.39 (dd; 2; J=6.5, 8.8; pyr-4-H) (in Me2 SO-D6).
EXAMPLE 5
Preparation of 3,4-HOPOCAM (Formula 10; m=3, n=4, X=Na): A procedure identical to that of the previous two examples was followed, with the exception that the amine used in this example was spermidine. The product, 3,4-HOPOCAM, was isolated by HPLC and obtained in about a 34% yield, mp 130°-135° C. + FAB Mass. Spec.: 557 (M+ +H, 100), 541 (65), 525 (19), 509 (4). 1 H NMR: δ 1.55 (bm; 6; CH2 CH2 CH2), 3.2-3.4 (bm; 8; CONCH2), 6.23 (m; 3; pyr-3- or 5-H), 6.55 (d; 3; J=8, pyr-5- or 3-H), 7.39 (t; 3; J=8, pyr-4-H), 8.74 (t; 2; J=7; CONH) (in Me2 SO-D6).
EXAMPLE 6
Preparation of 3,4,3-HOPOCAM (Formula 11; 1=n=3, m=4, R' is HOPO): The procedures of Examples 3, 4, and 5 was again followed, with spermidine providing the amine backbone. The product, 3,4,3-HOPOCAM, was isolated by HPLC and obtained in about a 15% yield. M.p. 135° C. + FAB Mass. Spec.: 773 (M+ +Na, 5), 751 (M+ +H, 86), 735 (100). 1 H NMR: δ 1.73 (bm; 8; CH2 CH2 CH2), 2.8-3.7 (bm; 12; CONCH2), 6.18 (m; 4; pyr-3- or 5-H), 6.53 (719 (47), 703 (22) (d; 4; J=7; pyr-5- or 3-H), 7.38 (t; 4; J=7; pyr-4-H), 8.75 (m; 2; CONH) 2.8 (in Me2 SO-D6).
EXAMPLE 7
Preparation of HOPOMECAM (Formula 12; Z=HOPO): The procedure of the previous four examples was followed, with tris aminomethylbenzene as the amine to be substituted with three HOPO ligands. The product, HOPOMECAM, was purified by HPLC and isolated in about a 17% yield. M.p. 135° C. dec. + FAB Mass. Spec.: 577 (M+ +H, 100), 561 (50), 545 (31). 1 H NMR: δ 4.41 (s; 3; CONCH2), 4.47 (s; 3; CONCH2), 6.36 (dd; 3; J=1, 6.9; pyr-3- or 5-H), 6.57 (dd; 3; J=1, 8.5; pyr-5- or 3-H), 7.19 (s; 3; C6 H3), 7.37 (dd; 3; J=6.9, 8.5; pyr-4-H), 9.35 (t; 3; J=5).
EXAMPLE 8
Preparation of DFHOPOCAM (Formula 13; j=1=n=2, k=m=5): The procedure of the previous example was followed, with desferrioxamine as the amine backbone. The product, DFHOPOCAM, was recrystallized in water and obtained in about a 56% yield. M.p. 141°-143° C. + FAB Mass. Spec.: 720 (M+ +Na, 23), 698 (M+ +H, 100), 682 (48). 1 H NMR: δ 1.14-1.86 (m; 18; CH2 CH2 CH2), 2.08 (s; 3; COCH3), 2.44 (t; 4; J=5.9; NHCOCH2), 2.74 (t; 4; J=5.9; NOHCOCH2), 3.16 (t; 4; J=6.4; CONHCH2), 3.59 (t; 6; J=6.9; CONOHCH2), 6.71 (d; 2; J=8.0; pyr-3- and 5-H), 7.46 (t; 1; J=8.0; pyr-4-H) (in CD3 OD).
EXAMPLE 9 Iron Removal Bioassay in Mice
DFHOPOCAM was tested for its effectiveness in removing iron from iron-loaded mice. The mice tested had undergone three transfusions over five days of heat-treated canine red blood cells. Both low i.p. doses (about 20 mg/kg) and high doses (about 200 mg/kg) were administered, in aqueous solution. Analysis of daily excreta during a five-day recovery period disclosed reversal of most of the damage to excretory pathways resulting from the excess metabolic iron.
At the lower dose, behavior was not affected, and necropsy failed to reveal any changes in the size or color of major organs. A favorable 11% decline in splenic iron (see Table 1) was not accompanied by a significant change in organ weight. That DFHOPOCAM was an effective chelator was substantiated by a 28% decrease in hepatic iron with only an 8% decline in hepatic weight. Excretion of iron via the feces was increased 21% accompanied by a minor 8% fall in fecal output. Urine production was stimulated 24% concurrently with a 39% increase in urinary iron.
The higher dose of DFHOPOCAM in general evoked dose-related responses. The decrease in water imbibition was about the same order of magnitude as that seen for the low dose. Behavior and major organs were not grossly affected. Spleen weight increased 25% (low dose was 4%) and iron content fell 17% (low dose was down 11%). Liver weight fell from 8% (low dose) to 14% and liver iron decreased from 28% (low dose) to 59%. Fecal output was depressed 24% with little change in iron content. On the other hand, urinary iron rose to a modest 93% (low dose was 39%) without much of a change in urine volume (-6%).
Potency of DFHOPOCAM was about 4.5 relative to Desferal. The major route of excretion was through the kidneys, and the source of iron was predominantly the liver for both low and high doses. Of a number of compounds tested, DFHOPOCAM was least toxic to the kidneys. Results are summarized in Table 1.
                                  TABLE 1                                 
__________________________________________________________________________
Changes in splenic, hepatic, fecal and urinary iron in transfused         
male mice treated with potential iron chelators for several days          
         Dose    Number       Percent Iron Changes vs. Control            
                                              Potency vs.                 
Test Compound                                                             
         mg/kg                                                            
             Route                                                        
                 Survivors                                                
                       Toxic Signs                                        
                              Spleen                                      
                                  Liver                                   
                                      Feces                               
                                          Urine                           
                                              Standard                    
__________________________________________________________________________
Desferrioxamine                                                           
         250 i.p.                                                         
                 240/240                                                  
                       none   ±2                                       
                                  -23 +7  +270                            
                                              1.0                         
Desferrioxamine                                                           
         250 i.p.                                                         
                 150/150                                                  
                       none   ±2                                       
                                  -28 +3  +234                            
                                              1.0                         
DFHOPOCAM                                                                 
          20 i.p.                                                         
                 10/10 none   -11 -28  +21                                
                                          +39 4.5                         
DFHOPOCAM                                                                 
         200 i.p.                                                         
                 10/10 water intake                                       
                              -17 -59 +4  +93 0.8                         
                       decreased                                          
__________________________________________________________________________
EXAMPLE 10
Preparation of the Ferric Ion Complex of 3-HOPOCAM (Fe2 L3, L=3-HOPOCAM): A solution of 155 mg (0.38 mmole) of Fe(NO3)3 9H2 O in 2 ml of water was added dropwise to a solution of 200 mg (0.57 mmole) of 1-hydroxy-2(1H)-pyridinone-6-carboxylic acid (Formula 7A) in 10 ml of water. A bright orange solid immediately precipitated, and the pH of the reaction mixture fell to 1.6. The pH was adjusted with 1M KOH to 7 and the precipitate was isolated by filtration and washed with water. The moist precipitate was dissolved in 15 ml of 1:1 MeOH-CH2 Cl2, and this mixture was filtered to remove a trace of dark brown insoluble material. Evaporation of the filtrate and drying of the residue in vacuo at 25° C. gave 172 mg (78%) of amorphous orange product. IR: 1678 (s), 1609 cm-1 (s).
Recrystallization of the Fe2 L3 complex from dichloromethane gave elongated crystals with thin diamond-shaped cross sections. Solution NMR indicated the presence of dichloromethane, and the density (1.55 g/cm3 in aqueous ZnCl2) and unit cell constants (see below) were consistent with the formulation C45 H42 N12 O18 Fe2.3CH2 Cl2. Apparently some solvent was lost prior to analysis. (Analysis: C, H, N, Fe2 O3 ; Cl calcd. 15.2, found 11.2.)
Orange-red hexagonal needles were obtained by evaporating a solution of amorphous material in 1:1 MeOH:CH2 Cl2 containing a small amount (1-2%) of water. Analysis (C48 H42 N12 Fe2.2CH3 OH.H2 O) C, H, N.
Crystallography: An Enraf-Nonius CAD4 diffractometer equipped with a Universal Low Temperature Device, a PDP 11/60 computer, and locally modified SDP software (see, e.g., B. A. Frenz and Assoc., "Structure Determination Package User's Guide," College Station, Texas (1982) were used. Monochromated CuK radiation (λ=1.5418 A) was used because of the large unit cells involved for both crystal forms isolated.
Precession photography and diffractometry were used to establish the space group of the CH2 Cl2 solvated crystals as P21 /c with room temperature dimensions a=22.203(4), b=13.125(2), c=42.06(4) Å, β=79.70(4)° and V=12059(12) Å3. The large cell volume indicates eight Fe2 L3 units per unit cell. Because of the large asymmetric unit, the structure of the monoclinic crystals was not pursued.
Precession photography of the hexagonal crystals indicated the space group to be either P61 or P65. The hexagonal needles visibly fractured several hours after being removed from solvent (density measurements suggest this is due to loss of one methanol of solvation). Thus after cleavage normal to the c-axis to give a -0.2 mm3 fragment, the data crystal was mounted in a thin-walled quartz capillary and maintained at -99°±3° C. [a=13.731(2) Å, c=48.430(5) Å, and V=7908(2) Å3, z=6]. The 7775 unique observed data were empirically corrected for absorption; rotation around the diffraction vector gave at most a 29% variation in intensity. Crystallographic data is summarized in Table 2.
Solution of the structure indicates that the compound consists of molecules containing two high-spin ferric ions and three 3-HOPOCAM ligands arranged such that the octahedral coordination requirement of each iron atom is satisfied by the oxygen atoms of three bidentate hydroxypyridonate groups. Each 3-HOPOCAM ligand bridges between the two iron atoms.
              TABLE 2                                                     
______________________________________                                    
Crystallographic summary for hexagonal                                    
crystals of Fe.sub.2 (C.sub.15 H.sub.14 N.sub.4 O.sub.6).sub.3.H.sub.2    
O.                                                                        
2CH.sub.3 OH(C.sub.47 H.sub.52 Fe.sub.2 N.sub.12 O.sub.21).               
______________________________________                                    
Formula weight         1232.7                                             
Space group            P6.sub.1                                           
a (A)                  13.731(2).sup.a                                    
c (A)                  48.430(5)                                          
Volume (A.sup.3)       7908(2)                                            
z. formula units/cell  6                                                  
Density (calc. g/cm.sup.3)                                                
                       1.553                                              
Density (obs. g/cm.sup.3)                                                 
                       1.51-1.55.sup.b                                    
Wavelength (A) CuK.sub.a                                                  
                       1.5418                                             
Range of 28 (°) 2-120                                              
Unique reflections measured, not                                          
                       7775                                               
systematically absent                                                     
Observed reflections.sup.c (n.sub.o)                                      
                       5077                                               
Refined parameters (n.sub.v)                                              
                       756                                                
Extinction parameter (refined)                                            
                       2.0(1) × 10.sup.-7                           
R.sup.d                0.044                                              
R.sub.w.sup.d          0.049                                              
R.sub.all.sup.d        0.110                                              
G.O.F..sup.d           1.40                                               
Largest e.sup.- /A.sup.3 in final                                         
                       0.47                                               
difference Fourier                                                        
______________________________________                                    
 .sup.a The e.s.d.'s of the last digit are shown in parentheses. Cell     
 constants were determined from the refinement of the setting angles for 2
 high angle reflections. The temperature was -99 ± 3° C.        
 .sup.b Three density determinations by flotation were performed. In      
 aqueous ZnCl.sub. 2 a value of 1.53 was obtained.                        
 Crystals exposed to air for several months gave D = 1.51 (aqueous CsCl)  
 suggesting loss of one methanol performula unit. The same crystals left  
 overnight in 1:2 MeOH/H.sub.2 O (+CsCl) had D = 1.55.                    
 .sup.c Reflections with F.sup.2 > σ(F.sup.2) were considered       
 observed and used in the leastsquared refinement.                        
 .sup.d Error indices are defined as follows: R = (Σ∥F.sub.
 |-|F.sub.c |)/Σw(|f.sub.o      
 |-|F.sub.c |).sup.2)/(n.sub.o -               
 n.sub.v)|.sup.1/2 where F.sub.o and F.sub.c are observed and    
 calcu lated structure factors, the weight w.sub.c = 4F.sup.2             
 /σ.sup.2 (F.sup.2) and the sum is over all observed                
 reflections.sup.c. R.sub.all is defined as is R except the sum is over al
 measured reflections.
EXAMPLE 11
Removal of Iron From Transferrin: The effectiveness of 3HOPOCAM as a ferri ion chelator was evaluated in terms of its potential for removing iron from transferrin. In order to account for the effect of proton competitio in the ligand strength comparisons, the relative ironbinding abilities of the ligands were ranked by the pM value, defined as -log [Fe+3 ] of pH 7.4 solution that is 10-5 M in total ligand and 10-6 M in total iron. The pM for 3HOPOCAM was determined (by binding competition experiments with EDTA) to be 21.7, about 4 to 14 units lower than the pM value for siderophores containing three bidentate catechol or hydroxamate groups. The corresponding pM for transferrin was found to be about 23.6 (assuming [HCO3 - ]=0.024M), so that from a thermodynamic standpoint, 3HOPOCAM would not be expected to be effective in in vivo iro removal from transferrin at lower (10 μM) concentrations of ligand. At the higher concentrations tested, however, the equilibrium shifted to favor the 3HOPOCAM complex (Fe2 L3), and 3HOPOCAM did in fact remove iron from transferrin at approximately mM concentrations; in 30 min., about 29% of the iron was removed by a 1.6 mM solution of 3HOPOCAM. Ligands incorporating more than two "HOPO" groups should be effective in removing iron from transferrin at even lower concentrations.
EXAMPLE 12
The novel chelating agents of the present invention were tested for their effectiveness in promoting excretion of 238 Pu(IV) in mice as follows. Groups of five mice each received an intravenous injection of 0. ml of 238 Pu(IV) in citrate buffer, 9250 Bq/kg body wt. One hour later 30 μmole/kg of ligand (120 μmole/kg of monomeric ligands) was injected intraperitoneally in 0.5 ml of saline. The mice were killed 24 h after the Pu injection, frozen, and dissected after partial thawing. The 238 Pu in skeleton, tissues, and separated excreta was determined by counting of the 234 U L xrays.
A test of acute toxicity was also carried out, as follows. Two mice were each given a single i.p. injection of 100, 500, or 1000 μmole/kg of ligand dissolved in 0.5 to 1.0 ml of saline at pH=7.5. Sparingly soluble ligands, dispersed by sonication, were given as finely divided suspensions. After 7 days observation, the mice were killed, selected tissues were removed and fixed for histopathological examination, and unusual findings at autopsy were recorded.
Results of the initial tests of potency and toxicity of the ligands tested are summarized in Table 3, which also includes data for the baseline ligand, CaNa3DTPA and the Puinjected controls (no ligands) killed at 1 hr or 24 hr after injection. Results using iron and zinc complexes of the ligands are summarized in Table 4. As illustrated by the data compile in Tables 3 and 4, all the novel chelating agents provided effective Pu removal, although HOPOsubstituted desferrioxamine proved to be the most effective Pu removal agent (86% of newly injected Pu excreted in 24 hr). Furthermore, none of the desferrioxamine derivatives proved to be acutely toxic, even at the relatively high dose of 1000 μmole/kg.
                                  TABLE 3                                 
__________________________________________________________________________
            Percent of injected .sup.238 Pu + S.D. at 24 hr.sup.b,c       
            Tissues                                                       
                           Residual                                       
                                Excreta                                   
                           soft Body    Feces and                         
            Liver                                                         
                 Skeleton                                                 
                      Kidneys                                             
                           tissue                                         
                                content                                   
                                    Urine                                 
                                        GI contents                       
__________________________________________________________________________
Test Legands                                                              
3,4,3-HOPOCAM*                                                            
            8.9 ± 1.7                                                  
                 7.5 ± 0.7                                             
                      0.2  1.6 ± 0.6                                   
                                19  24. 57                                
3,4-HOPOCAM*                                                              
            17. ± 4.6                                                  
                 9.5 ± 3.5                                             
                      0.6  5.6 ± 1.2                                   
                                36  7.5 56                                
HOPO--MECAM**                                                             
            18. ± 6.3                                                  
                 17. ± 2.5                                             
                      1.8  10. ± 1.8                                   
                                46  9.6 44                                
3-HOPOCAM   8.7 ± 1.2                                                  
                 17. ± 2.8                                             
                      1.4  11. ± 0.8                                   
                                38  8.7 53                                
HOPO--CO.sub.2 H                                                          
            52. ± 4.6                                                  
                 24. ± 5.1                                             
                      1.2  6.3 ± 1.6                                   
                                83  7.0 9.6                               
HOPO--COMe.sub.2                                                          
            56. ± 6.3                                                  
                 27. ± 5.5                                             
                      1.4  5.9 ± 1.2                                   
                                87  4.5 8.6                               
DFHOPOCAM   4.6 ± 1.2                                                  
                 7.4 ± 0.8                                             
                      0.3  1.7 ± 0.3                                   
                                14  40  46                                
Baseline Ligand                                                           
CaNa.sub.3 --DTPA                                                         
             16 ± 2.8                                                  
                 11 ± 1.2                                              
                      0.4  3.8 ± 1.5                                   
                                30  70                                    
.sup.238 Pu-injected Controls                                             
1-hr Controls                                                             
             30 ± 7.4                                                  
                 24 ± 4.4                                              
                      2.7   37 ± 7.1                                   
                                94  1.1 4.8                               
24-hr Controls                                                            
             49 ± 8.3                                                  
                 32 ± 7.9                                              
                      20   7.7 ± 2.0                                   
                                92  4.7 4.1                               
Desferrioxamine                                                           
            19 ± 13                                                    
                 20 ± 11                                               
                      1.8  4.5 ± 1.4                                   
                                46  40  15                                
__________________________________________________________________________
 .sup.a Single or double asterisks indicate acutely toxic (50% to 100%    
 lethality) in 7 days after a single i.p. injection of 1000 or 500        
 μmole/kg, respectively.                                               
 .sup.b S.D. = [Σ dev.sup.2 /(n  1)].sup.1/2. Where S.D. is not     
 shown, samples were pooled for 5mouse group. Data were normalized to 100%
 material recovery; discrepancies are due to rounding.                    
 .sup.c Ligand was administered (30 μmole/kg, i.p.) at 1 hr and mice   
 were killed at 24 hr after injection (i.v.) of .sup.238 Pu(IV) citrate.  
 Dosage of monomers, HOPO--CO.sub.2 H and HOPO--COMe.sub.2, was 120       
 μmole/kg.                                                             

                                  TABLE 4                                 
__________________________________________________________________________
            Percent of injected .sup.238 Pu + S.D. at 24 hr.sup.b,c       
            Tissues                                                       
                           Residual                                       
                                Excreta                                   
                           soft Body    Feces and                         
            Liver                                                         
                 Skeleton                                                 
                      Kidneys                                             
                           tissue                                         
                                content                                   
                                    Urine                                 
                                        GI contents                       
__________________________________________________________________________
Test Legands                                                              
Iron Complex                                                              
3,4,3-HOPOCAM--Fe                                                         
            5.1 ± 2.2                                                  
                 6.0 ± 0.5                                             
                      0.1  2.3 ± 0.5                                   
                                13  19  68                                
Zinc Complexes                                                            
3,4,3-HOPOCAM--Zn**                                                       
            4.0 ± 0.8                                                  
                 9.6 ± 0.6                                             
                      0.3  2.4 ± 0.6                                   
                                16  21  63                                
3,4-HOPOCAM--Zn**                                                         
            13. ± 3.8                                                  
                 12. ± 2.2                                             
                      3.1  5.1 ± 1.4                                   
                                34  14  52                                
3-HOPOCam--Zn**                                                           
            5.5 ± 0.8                                                  
                 16. ± 2.4                                             
                      0.4  12. ± 2.6                                   
                                35  5.2 60                                
Native Ligand                                                             
3,4,3-HOPOCAM*                                                            
            8.9 ± 1.7                                                  
                 7.5 ± 0.7                                             
                      0.2  1.6 ± 0.6                                   
                                19  24  57                                
__________________________________________________________________________
 .sup.a Single or double asterisks indicate acutely toxic (50% to 100%    
 lethality) in 7 days after a single i.p. injection of 1000 or 500        
 μmole/kg, respectively.                                               
 .sup.b S.D. = [Σ dev.sup.2 /(n  1)].sup.1/2. Where S.D. is not     
 shown, samples were pooled for 5mouse group. Data were normalized to 100%
 material recovery; discrepancies are due to rounding.                    
 .sup.c Ligand was administered (30 μmole/kg, i.p.) at 1 hr. and mice  
 were killed at 24 hr. after injection (i.v.) of .sup.238 Pu(IV) citrate.
While the various aspects of the inventive compounds and processes have been described in conjunction with the preferred specific embodiments thereof, it is to be understood that all synthetic steps, reagents and reaction conditions reasonably equivalent to those described explicitly are also within the scope of this invention, as are all reasonably equivalent structures. The description given above is intended to be illustrative and not limitative of the various embodiments of this invention, the scope of which is defined by the appended claims.

Claims (2)

We claim:
1. A chelating agent having the structure: ##STR12## wherein R is a hydroxy group or ##STR13## where R1 and R2 are selected from the group consisting of H, --CH3, --CH2 CH3 and --CH2 --φ, and X is either hydrogen, an alkali metal ion, or a quaternary ammonium ion.
2. The chelating agent of claim 1, wherein R is ##STR14##
US06/796,815 1985-11-12 1985-11-12 Hydroxypyridonate chelating agents Expired - Lifetime US4698431A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US06/796,815 US4698431A (en) 1985-11-12 1985-11-12 Hydroxypyridonate chelating agents

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US06/796,815 US4698431A (en) 1985-11-12 1985-11-12 Hydroxypyridonate chelating agents

Publications (1)

Publication Number Publication Date
US4698431A true US4698431A (en) 1987-10-06

Family

ID=25169129

Family Applications (1)

Application Number Title Priority Date Filing Date
US06/796,815 Expired - Lifetime US4698431A (en) 1985-11-12 1985-11-12 Hydroxypyridonate chelating agents

Country Status (1)

Country Link
US (1) US4698431A (en)

Cited By (33)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4780238A (en) * 1983-08-25 1988-10-25 The United States Of America As Represented By The United States Department Of Energy Natural chelating agents for radionuclide decorporation
US4912118A (en) * 1983-09-23 1990-03-27 National Research Development Corporation Pharmaceutical compositions
EP0397409A1 (en) * 1989-05-08 1990-11-14 Btg International Limited The stabilization of organic compounds
US5010191A (en) * 1985-08-19 1991-04-23 The Regents Of The University Of California Imaging agents for in vivo magnetic resonance and scintigraphic imaging
US5177068A (en) * 1984-04-19 1993-01-05 National Research Development Corporation Pharmaceutical compositions
USRE34313E (en) * 1983-09-23 1993-07-13 National Research Development Corporation Pharmaceutical compositions
JPH05246992A (en) * 1983-09-23 1993-09-24 British Technol Group Ltd Pharmaceutical composition effective to reduce toxic concentration of metals in patients' body consisting of 1-hydroxypirid-2-one or salt thereof
WO1997000245A1 (en) * 1995-06-14 1997-01-03 The Regents Of The University Of California 3-hydroxy-2(1h)-pyridinone chelating agents
US5622996A (en) * 1995-02-17 1997-04-22 Regents Of The University Of California Polymer-supported sulfonated catechol and linear catechol amide ligands and their use in selective metal ion removal and recovery from aqueous solutions
US5624901A (en) * 1994-04-15 1997-04-29 The Regents Of The University Of California 3-hydroxy-2(1H)-pyridinone chelating agents
WO1997031296A1 (en) * 1996-02-26 1997-08-28 Polaroid Corporation Image-recording element
US6221476B1 (en) 1999-06-11 2001-04-24 Ibc Advanced Technologies, Inc. Polymeric membranes functionalized with polyhydroxypyridinone ligands
US6232265B1 (en) 1999-06-11 2001-05-15 Ibc Advanced Technologies, Inc. Particulate solid supports functionalized with polyhydroxypyridinone ligands
US20050008570A1 (en) * 2001-08-13 2005-01-13 The Regents Of The University Of California Hydroxypyridonate and hydroxypyrimidinone chelating agents
US20070100024A1 (en) * 2005-10-31 2007-05-03 Feng Gu Modified colorants and inkjet ink compositions comprising modified colorants
WO2007121453A3 (en) * 2006-04-17 2008-07-31 Univ California 2-hydroxy-1-oxo 1,2 dihydro isoquinoline chelating agents
US20080264298A1 (en) * 2007-04-30 2008-10-30 Burns Elizabeth G Pigment dipsersions comprising functionalized non-polymeric dispersants
US20090229489A1 (en) * 2008-03-17 2009-09-17 Feng Gu Modified pigments having reduced phosphate release, and dispersions and inkjet ink compositions therefrom
US20100015725A1 (en) * 2006-07-10 2010-01-21 The Regents Of The University Of California Luminescent 1-hydroxy-2-pyridinone chelates of lanthanides
US20110189088A1 (en) * 2009-12-24 2011-08-04 Lumiphore, Inc. Radiopharmaceutical complexes
EP2412371A1 (en) * 2006-07-13 2012-02-01 Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center Compositions comprising iron chelators (deferiprone/deferasirox) for use in the treatment of mucormycosis and other fungal diseases
US20150104385A1 (en) * 2012-05-11 2015-04-16 Algeta Asa Radio-pharmaceutical complexes
US9273059B2 (en) 2009-08-24 2016-03-01 Lumiphore, Inc. Macrocyclic HOPO chelators
WO2016106241A1 (en) * 2014-12-22 2016-06-30 Lumiphore, Inc. Functionalized linear ligands and complexes thereof
AU2013202984B2 (en) * 2006-07-10 2016-08-11 The Regents Of The University Of California Luminescent 1-hydroxy-2-pyridinone chelates of lanthanides
US10239878B2 (en) 2016-09-02 2019-03-26 Lumiphore, Inc. Macrocyclic ligands with pendant chelating moieties and complexes thereof
US10982136B2 (en) 2016-02-26 2021-04-20 The Regents Of The University Of California Ligand-sensitized lanthanide nanocrystals as ultraviolet downconverters
US11235076B2 (en) 2016-08-29 2022-02-01 Fred Hutchinson Cancer Research Center Chelating platform for delivery of radionuclides
US11453652B2 (en) 2013-03-15 2022-09-27 Lumiphore, Inc. Di-macrocycles
US11684614B2 (en) 2016-09-06 2023-06-27 The Regents Of The University Of California Formulations of hydroxypyridonate actinide/lanthanide decorporation agents
EP4290532A2 (en) 2016-09-29 2023-12-13 The Regents of the University of California Separation of metal ions by liquid-liquid extraction
US11951188B2 (en) 2018-03-07 2024-04-09 Lumiphore, Inc. Macrocyclic ligands with pendant chelating moieties and complexes thereof
US12479792B2 (en) 2016-09-29 2025-11-25 The Regents Of The University Of California Compositions of chelating molecules

Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3864334A (en) * 1973-11-02 1975-02-04 Stauffer Chemical Co Derivatives of certain n-oxypridyl geranyl ethers and their use in controlling insects
US3928616A (en) * 1973-11-02 1975-12-23 Stauffer Chemical Co Derivatives of certain N-oxypyridyl geranyl ethers used in controlling insects
US4063927A (en) * 1975-08-07 1977-12-20 The Procter & Gamble Company Disulfoxide abscission agents
US4181654A (en) * 1978-07-24 1980-01-01 The United States Of America As Represented By The United States Department Of Energy 2,3-Dihydroxybenzoic acid amides of tetraazaalkanes and tetaaza cycloalkanes
US4293542A (en) * 1976-05-03 1981-10-06 L'oreal Cosmetic composition for imparting to human skin a coloration resembling a natural tan
US4309305A (en) * 1978-07-24 1982-01-05 The United States As Represented By The United States Department Of Energy In vitro removal of actinide (IV) ions
US4396766A (en) * 1982-04-28 1983-08-02 Olin Corporation Process for producing sodium and zinc pyrithione
US4397867A (en) * 1981-06-19 1983-08-09 Ciba-Geigy Corporation Treatment of arthritic complaints
US4419365A (en) * 1981-12-21 1983-12-06 Ciba-Geigy Corporation Method of treating Alzheimer's disease
US4442305A (en) * 1981-08-24 1984-04-10 The United States Of America As Represented By The United States Department Of Energy Polycatecholamide chelating agents
US4530963A (en) * 1982-08-20 1985-07-23 Devoe-Holbein International, N.V. Insoluble chelating compositions
US4543213A (en) * 1978-07-24 1985-09-24 The United States Of America As Represented By The United States Department Of Energy Process for preparing 2,3-dihydroxybenzoic acid amides of tetraazaalkanes and cycloalkanes

Patent Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3864334A (en) * 1973-11-02 1975-02-04 Stauffer Chemical Co Derivatives of certain n-oxypridyl geranyl ethers and their use in controlling insects
US3928616A (en) * 1973-11-02 1975-12-23 Stauffer Chemical Co Derivatives of certain N-oxypyridyl geranyl ethers used in controlling insects
US4063927A (en) * 1975-08-07 1977-12-20 The Procter & Gamble Company Disulfoxide abscission agents
US4293542A (en) * 1976-05-03 1981-10-06 L'oreal Cosmetic composition for imparting to human skin a coloration resembling a natural tan
US4181654A (en) * 1978-07-24 1980-01-01 The United States Of America As Represented By The United States Department Of Energy 2,3-Dihydroxybenzoic acid amides of tetraazaalkanes and tetaaza cycloalkanes
US4309305A (en) * 1978-07-24 1982-01-05 The United States As Represented By The United States Department Of Energy In vitro removal of actinide (IV) ions
US4543213A (en) * 1978-07-24 1985-09-24 The United States Of America As Represented By The United States Department Of Energy Process for preparing 2,3-dihydroxybenzoic acid amides of tetraazaalkanes and cycloalkanes
US4397867A (en) * 1981-06-19 1983-08-09 Ciba-Geigy Corporation Treatment of arthritic complaints
US4442305A (en) * 1981-08-24 1984-04-10 The United States Of America As Represented By The United States Department Of Energy Polycatecholamide chelating agents
US4419365A (en) * 1981-12-21 1983-12-06 Ciba-Geigy Corporation Method of treating Alzheimer's disease
US4396766A (en) * 1982-04-28 1983-08-02 Olin Corporation Process for producing sodium and zinc pyrithione
US4530963A (en) * 1982-08-20 1985-07-23 Devoe-Holbein International, N.V. Insoluble chelating compositions

Non-Patent Citations (10)

* Cited by examiner, † Cited by third party
Title
Durbin, P. W. et al., "Kinetics of Plutonium Deposition in the Mouse", Ann. Rpt. 1983-4, Biology and Medicine Division, Lawrence Berkeley Lab. (Apr. 1985).
Durbin, P. W. et al., "New Sequestering Agents for the Actinides . . . ", Ann. Rpt. 1983-4, Biology and Medicine Division, Lawrence Berkeley Lab. (Apr. 1985).
Durbin, P. W. et al., Kinetics of Plutonium Deposition in the Mouse , Ann. Rpt. 1983 4, Biology and Medicine Division, Lawrence Berkeley Lab. (Apr. 1985). *
Durbin, P. W. et al., New Sequestering Agents for the Actinides . . . , Ann. Rpt. 1983 4, Biology and Medicine Division, Lawrence Berkeley Lab. (Apr. 1985). *
Raymond et al., CA 103: 192911n. *
Raymond, K. N., Specific Sequestering Agents for Iron and Actinides, in Environmental Inorganic Chemistry (VCH Publishers, Inc. 1985). *
Riley, P. E. et al., "Specific Sequestering Agents for the Actinides.9.Synthesis of Metal Complexes of 1-Hydroxy-2-Pyridinone . . . ," Inorganic Chemistry, 22 (1983), pp. 3940 et seq.
Riley, P. E. et al., Specific Sequestering Agents for the Actinides.9.Synthesis of Metal Complexes of 1 Hydroxy 2 Pyridinone . . . , Inorganic Chemistry, 22 (1983), pp. 3940 et seq. *
Scarrow et al., CA 102: 124493g. *
Scarrow, R. C. et al., Ferric Ion Sequestering Agents . . . , Inorganic Chemistry, 24 (1985), pp. 954 et seq. *

Cited By (56)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4780238A (en) * 1983-08-25 1988-10-25 The United States Of America As Represented By The United States Department Of Energy Natural chelating agents for radionuclide decorporation
USRE34313E (en) * 1983-09-23 1993-07-13 National Research Development Corporation Pharmaceutical compositions
US4912118A (en) * 1983-09-23 1990-03-27 National Research Development Corporation Pharmaceutical compositions
JPH05246992A (en) * 1983-09-23 1993-09-24 British Technol Group Ltd Pharmaceutical composition effective to reduce toxic concentration of metals in patients' body consisting of 1-hydroxypirid-2-one or salt thereof
US5104865A (en) * 1983-09-23 1992-04-14 National Research Development Corporation Iron complexes of hydroxypyridones useful for treating iron overload
US5177068A (en) * 1984-04-19 1993-01-05 National Research Development Corporation Pharmaceutical compositions
US5010191A (en) * 1985-08-19 1991-04-23 The Regents Of The University Of California Imaging agents for in vivo magnetic resonance and scintigraphic imaging
US5185319A (en) * 1989-05-08 1993-02-09 National Research Development Corporation Stabilization of organic compounds
EP0397409A1 (en) * 1989-05-08 1990-11-14 Btg International Limited The stabilization of organic compounds
US5624901A (en) * 1994-04-15 1997-04-29 The Regents Of The University Of California 3-hydroxy-2(1H)-pyridinone chelating agents
US5892029A (en) * 1994-04-15 1999-04-06 The Regents Of The University Of California 3-hydroxy-2(1H)-pyridinone chelating agents
US5622996A (en) * 1995-02-17 1997-04-22 Regents Of The University Of California Polymer-supported sulfonated catechol and linear catechol amide ligands and their use in selective metal ion removal and recovery from aqueous solutions
WO1997000245A1 (en) * 1995-06-14 1997-01-03 The Regents Of The University Of California 3-hydroxy-2(1h)-pyridinone chelating agents
WO1997031296A1 (en) * 1996-02-26 1997-08-28 Polaroid Corporation Image-recording element
US6221476B1 (en) 1999-06-11 2001-04-24 Ibc Advanced Technologies, Inc. Polymeric membranes functionalized with polyhydroxypyridinone ligands
US6432313B2 (en) 1999-06-11 2002-08-13 Ibc Advanced Technologies, Inc. Method for concentrating, removing, and separating selected ions from source solutions using particulate solid supports functionalized with polyhydroxypyridinone ligands
US6232265B1 (en) 1999-06-11 2001-05-15 Ibc Advanced Technologies, Inc. Particulate solid supports functionalized with polyhydroxypyridinone ligands
US7718781B2 (en) 2001-08-13 2010-05-18 The Regents Of The University Of California Hydroxypyridonate and hydroxypyrimidinone chelating agents
US20050008570A1 (en) * 2001-08-13 2005-01-13 The Regents Of The University Of California Hydroxypyridonate and hydroxypyrimidinone chelating agents
US8858695B2 (en) 2005-10-31 2014-10-14 Cabot Corporation Modified colorants and inkjet ink compositions comprising modified colorants
US9963592B2 (en) 2005-10-31 2018-05-08 Cabot Corporation Modified colorants and inkjet ink compositions comprising modified colorants
US9732227B2 (en) 2005-10-31 2017-08-15 Cabot Corporation Modified colorants and inkjet ink compositions comprising modified colorants
US20070100023A1 (en) * 2005-10-31 2007-05-03 Burns Elizabeth G Modified colorants and inkjet ink compositions comprising modified colorants
US9725598B2 (en) 2005-10-31 2017-08-08 Cabot Corporation Modified colorants and inkjet ink compositions comprising modified colorants
US20070100024A1 (en) * 2005-10-31 2007-05-03 Feng Gu Modified colorants and inkjet ink compositions comprising modified colorants
WO2007121453A3 (en) * 2006-04-17 2008-07-31 Univ California 2-hydroxy-1-oxo 1,2 dihydro isoquinoline chelating agents
US20100015725A1 (en) * 2006-07-10 2010-01-21 The Regents Of The University Of California Luminescent 1-hydroxy-2-pyridinone chelates of lanthanides
US9556122B2 (en) 2006-07-10 2017-01-31 The Regents Of The University Of California Luminescent 1-hydroxy-2-pyridinone chelates of lanthanides
AU2013202984B2 (en) * 2006-07-10 2016-08-11 The Regents Of The University Of California Luminescent 1-hydroxy-2-pyridinone chelates of lanthanides
EP2511266A1 (en) 2006-07-10 2012-10-17 The Regents of The University of California Luminescent 1-Hydroxy-2-Pyridinone Chelates of Lanthanides
US8557601B2 (en) 2006-07-10 2013-10-15 The Regents Of The University Of California Luminescent 1-hydroxy-2-pyridinone chelates of lanthanides
EP2412371A1 (en) * 2006-07-13 2012-02-01 Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center Compositions comprising iron chelators (deferiprone/deferasirox) for use in the treatment of mucormycosis and other fungal diseases
US8133311B2 (en) 2007-04-30 2012-03-13 Cabot Corporation Pigment dipsersions comprising functionalized non-polymeric dispersants
US20080264298A1 (en) * 2007-04-30 2008-10-30 Burns Elizabeth G Pigment dipsersions comprising functionalized non-polymeric dispersants
US7819962B2 (en) 2008-03-17 2010-10-26 Cabot Corporation Modified pigments having reduced phosphate release, and dispersions and inkjet ink compositions therefrom
US20090229489A1 (en) * 2008-03-17 2009-09-17 Feng Gu Modified pigments having reduced phosphate release, and dispersions and inkjet ink compositions therefrom
US9273059B2 (en) 2009-08-24 2016-03-01 Lumiphore, Inc. Macrocyclic HOPO chelators
US10352938B2 (en) 2009-08-24 2019-07-16 Lumiphore, Inc. Macrocyclic HOPO chelators
US20110189088A1 (en) * 2009-12-24 2011-08-04 Lumiphore, Inc. Radiopharmaceutical complexes
EP3263562A1 (en) 2009-12-24 2018-01-03 Lumiphore, Inc. Radiopharmaceutical complexes
US20150104385A1 (en) * 2012-05-11 2015-04-16 Algeta Asa Radio-pharmaceutical complexes
US11453652B2 (en) 2013-03-15 2022-09-27 Lumiphore, Inc. Di-macrocycles
WO2016106241A1 (en) * 2014-12-22 2016-06-30 Lumiphore, Inc. Functionalized linear ligands and complexes thereof
US10434186B2 (en) 2014-12-22 2019-10-08 Lumiphore, Inc. Functionalized linear ligands and complexes thereof
US10982136B2 (en) 2016-02-26 2021-04-20 The Regents Of The University Of California Ligand-sensitized lanthanide nanocrystals as ultraviolet downconverters
US11235076B2 (en) 2016-08-29 2022-02-01 Fred Hutchinson Cancer Research Center Chelating platform for delivery of radionuclides
US12257325B2 (en) 2016-08-29 2025-03-25 Fred Hutchinson Cancer Research Center Chelating platform for delivery of radionuclides
US10239878B2 (en) 2016-09-02 2019-03-26 Lumiphore, Inc. Macrocyclic ligands with pendant chelating moieties and complexes thereof
US11603371B2 (en) 2016-09-02 2023-03-14 Lumiphore, Inc. Macrocyclic ligands with pendant chelating moieties and complexes thereof
US11684614B2 (en) 2016-09-06 2023-06-27 The Regents Of The University Of California Formulations of hydroxypyridonate actinide/lanthanide decorporation agents
US12268678B2 (en) 2016-09-06 2025-04-08 The Regents Of The University Of California Formulations of hydroxypyridonate actinide/lanthanide decorporation agents
EP4290532A2 (en) 2016-09-29 2023-12-13 The Regents of the University of California Separation of metal ions by liquid-liquid extraction
US12002595B2 (en) * 2016-09-29 2024-06-04 The Regents Of The University Of California Separation of metal ions by liquid-liquid extraction
US12479792B2 (en) 2016-09-29 2025-11-25 The Regents Of The University Of California Compositions of chelating molecules
US11951188B2 (en) 2018-03-07 2024-04-09 Lumiphore, Inc. Macrocyclic ligands with pendant chelating moieties and complexes thereof
US12440584B2 (en) 2018-03-07 2025-10-14 Lumiphore, Inc. Macrocyclic ligands with pendant chelating moieties and complexes thereof

Similar Documents

Publication Publication Date Title
US4698431A (en) Hydroxypyridonate chelating agents
US5624901A (en) 3-hydroxy-2(1H)-pyridinone chelating agents
RU2073005C1 (en) Metal chelate compound
DE3625417C2 (en) Tetraazacyclododecane derivatives
White et al. Specific sequestering agents for the actinides. 16. Synthesis and initial biological testing of polydentate oxohydroxypyridinecarboxylate ligands
US5262532A (en) Paramagnetic metalloporphyrins as contrast agents for magnetic resonance imaging
US4442305A (en) Polycatecholamide chelating agents
JP2877844B2 (en) Macrocyclic polyaza-compounds having 5- or 6-membered rings, process for their preparation, and NMR-, X-ray, radiation-diagnosis and radioactivity- and radiation-therapeutic agents containing them and processes for the preparation of these agents
JP2953670B2 (en) Heterocyclic chelating agent
CA2156158A1 (en) Meso-tetraphenyl porphyrin complex compounds, process for preparing the same and pharmaceuticals containing the same
DE69314613T2 (en) NEW CHELATION AGENT, COMPLEX COMPOUNDS CONSTRUCTED FROM THIS AGENT AND METAL ATOMS, AND DIAGNOSTIC AGENTS CONTAINING THESE COMPOUNDS
Santos et al. Bifunctional 3-hydroxy-4-pyridinone derivatives as potential pharmaceuticals: Synthesis, complexation with Fe (III), Al (III) and Ga (III) and in vivo evaluation with 67Ga
EP0178743A2 (en) Novel tritium labelled N-mustard type compounds and a process for their production
EP0883601B1 (en) Calixarenes and their use for sequestration of metals
EP0840727B1 (en) 3-hydroxy-2(1h)-pyridinone chelating agents
US6342634B2 (en) Calixarenes and their use for sequestration of metals
DE4311023C2 (en) Bifunctional chalcogen atom-interrupted chelating agents of type XN¶1¶S¶1¶O¶1¶ for radioactive isotopes, their metal complexes, processes for their preparation and pharmaceutical compositions containing them
AU2010246323A1 (en) Cycloalkyl derivatives of 3-hydroxy-4- pyridinones
Chaves et al. Alkylaryl-amino derivatives of 3-hydroxy-4-pyridinones as aluminium chelating agents with potential clinical application
JP2519205B2 (en) All-cis-1,3,5-triamino-2,4,6-cyclohexanetriol derivative
Costero et al. Synthesis of a new allosteric carrier containing three conformationally related subunits
EP0540975B1 (en) Diethylenetriamine derivatives and their use for diagnostic and therapeutic purposes
US20070185072A1 (en) Nitrogeneous polycyclic derivatives useful as chelators of metal ions and their applications
DE69913368T2 (en) CHELATORS FOR RADIOIMMUNOTHERAPY
JP7461092B2 (en) Novel compound and MRI contrast agent containing it

Legal Events

Date Code Title Description
AS Assignment

Owner name: UNITED STATES OF AMERICA, AS REPRESENTED BY THE DE

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST.;ASSIGNORS:RAYMOND, KENNETH N.;SCARROW, ROBERT C.;WHITE, DAVID L.;REEL/FRAME:004642/0143;SIGNING DATES FROM 19851105 TO 19851106

STCF Information on status: patent grant

Free format text: PATENTED CASE

FPAY Fee payment

Year of fee payment: 4

FPAY Fee payment

Year of fee payment: 8

FPAY Fee payment

Year of fee payment: 12